d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila.
d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila.
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DOI：
10.1111/j.1474-9726.2009.00504.x
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发表时间：
2009-09
期刊：
影响因子：
7.8
通讯作者：
Bodmer R
中科院分区：
文献类型：
--
作者：
Wessells R;Fitzgerald E;Piazza N;Ocorr K;Morley S;Davies C;Lim HY;Elmén L;Hayes M;Oldham S;Bodmer R
dTOR（雷帕霉素靶点）和dFoxo对营养环境的变化做出反应，在多种组织类型中诱导广泛的反应。dTOR和dFoxo都已被证明可以控制与年龄相关的心功能下降率。在这里，我们表明Eif4e结合蛋白（d4eBP）足以保护长期心脏功能免受年龄相关的下降，并且dEif4e的上调足以概括高dTOR或胰岛素信号传导的作用。我们还提供了证据表明，d4eBP在心肌中组织自主地作用于dTOR和dFoxo的下游，在那里它增强了心脏的应激抵抗力，并维持了正常的心率和肌源性节律。dTOR和胰岛素信号传导的另一种效应物dS6K可能通过其在胰岛素产生细胞（IPC）中的活性（可能通过调节dilp2表达）非自主地影响心脏衰老。因此，升高心脏组织中的d4eBP活性代表了用于减缓或逆转由正常老化引起的心脏功能变化的有效器官特异性手段。
dTOR (target of rapamycin) and dFoxo respond to changes in the nutritional environment to induce a broad range of responses in multiple tissue types. Both dTOR and dFoxo have been demonstrated to control the rate of age-related decline in cardiac function. Here, we show that the Eif4e-binding protein (d4eBP) is sufficient to protect long-term cardiac function against age-related decline and that up-regulation of dEif4e is sufficient to recapitulate the effects of high dTOR or insulin signaling. We also provide evidence that d4eBP acts tissue-autonomously and downstream of dTOR and dFoxo in the myocardium, where it enhances cardiac stress resistance and maintains normal heart rate and myogenic rhythm. Another effector of dTOR and insulin signaling, dS6K, may influence cardiac aging non-autonomously through its activity in the insulin-producing cells (IPCs), possibly by regulating dilp2 expression. Thus, elevating d4eBP activity in cardiac tissue represents an effective organ-specific means for slowing or reversing cardiac functional changes brought about by normal aging.